LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort

in Frontiers in Neurology (2021), 12

Background: Pathogenic variants in the Leucine-rich repeat kinase 2 ( LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2 -linked PD is clinically indistinguishable ... [more ▼]

Background: Pathogenic variants in the Leucine-rich repeat kinase 2 ( LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2 -linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions. Objective: To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data. Methods: Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with LRRK2 -linked PD, 200 with LRRK2 pathogenic variants but without PD, 100 PD patients with pathogenic variants in the GBA or PRKN genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants. Results: The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn \&Yahr, and Schwab \& England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021). Conclusions: LIPAD is a large-scale international scientific effort focusing on deep phenotyping of LRRK2 -linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivity Clinical Trial Registration: ClinicalTrials.gov , NCT04214509. [less ▲]

Development and Application of Liquid Chromatographic Retention Time Indices in HRMS-Based Suspect and Nontarget Screening

in Analytical Chemistry (2021), 93(33), 11601--11611

There is an increasing need for comparable and harmonized retention times (tR) in liquid chromatography (LC) among different laboratories, to provide supplementary evidence for the identity of compounds ... [more ▼]

There is an increasing need for comparable and harmonized retention times (tR) in liquid chromatography (LC) among different laboratories, to provide supplementary evidence for the identity of compounds in high-resolution mass spectrometry (HRMS)-based suspect and nontarget screening investigations. In this study, a rigorously tested, flexible, and less system-dependent unified retention time index (RTI) approach for LC is presented, based on the calibration of the elution pattern. Two sets of 18 calibrants were selected for each of ESI+ and ESI-based on the maximum overlap with the retention times and chemical similarity indices from a total set of 2123 compounds. The resulting calibration set, with RTI set to range between 1 and 1000, was proposed as the most appropriate RTI system after rigorous evaluation, coordinated by the NORMAN network. The validation of the proposed RTI system was done externally on different instrumentation and LC conditions. The RTI can also be used to check the reproducibility and quality of LC conditions. Two quantitative structure−retention relationship (QSRR)-based models were built based on the developed RTI systems, which assist in the removal of false-positive annotations. The applicability domains of the QSRR models allowed completing the identification process with higher confidence for substances within the domain, while indicating those substances for which results should be treated with caution. The proposed RTI system was used to improve confidence in suspect and nontarget screening and increase the comparability between laboratories as demonstrated for two examples. All RTI-related calculations can be performed online at http://rti.chem.uoa.gr/. [less ▲]

Visualisation Techniques for Consent: Finding Common Ground in Comic Art with Indigenous Populations

in 2021 IEEE European Symposium on Security and Privacy Workshops (EuroS&PW) (2021)

With emerging technologies such as genome research and the digitization of health records comes the need for new models of informed consent. In this climate of innovation people are often prone to explore ... [more ▼]

With emerging technologies such as genome research and the digitization of health records comes the need for new models of informed consent. In this climate of innovation people are often prone to explore the latest technological advancement as possible solutions, including for informed consent. In this paper, we present the design and evaluation of a so-called low-tech informed consent solution that was designed specifically for the informational and cultural needs of a vulnerable indigenous population, i.e., the San of South Africa. This low-tech solution took the form of a comic and, although it could enhance understanding and identification, the costs and labour intensity of comic design and the deriving limitations on its scalability should be critically considered in the light of a digitised and more standardized solution. [less ▲]

Don’t Put the Cart Before the Horse – Effective Incident Handling Under GDPR and NIS Directive

in Friedewald, Michael; Schiffner, Stefan; Krenn, Stephan (Eds.) Privacy and Identity Management (2021)

Towards Exploring the Limitations of Active Learning: An Empirical Study

in The 36th IEEE/ACM International Conference on Automated Software Engineering. (2021)

Deep neural networks (DNNs) are being increasingly deployed as integral parts of software systems. However, due to the complex interconnections among hidden layers and massive hyperparameters, DNNs ... [more ▼]

Deep neural networks (DNNs) are being increasingly deployed as integral parts of software systems. However, due to the complex interconnections among hidden layers and massive hyperparameters, DNNs require being trained using a large number of labeled inputs, which calls for extensive human effort for collecting and labeling data. Spontaneously, to alleviate this growing demand, a surge of state-of-the-art studies comes up with different metrics to select a small yet informative dataset for the model training. These research works have demonstrated that DNN models can achieve competitive performance using a carefully selected small set of data. However, the literature lacks proper investigation of the limitations of data selection metrics, which is crucial to apply them in practice. In this paper, we fill this gap and conduct an extensive empirical study to explore the limits of selection metrics. Our study involves 15 selection metrics evaluated over 5 datasets (2 image classification tasks and 3 text classification tasks), 10 DNN architectures, and 20 labeling budgets (ratio of training data being labeled). Our findings reveal that, while selection metrics are usually effective in producing accurate models, they may induce a loss of model robustness (against adversarial examples) and resilience to compression. Overall, we demonstrate the existence of a trade-off between labeling effort and different model qualities. This paves the way for future research in devising selection metrics considering multiple quality criteria. [less ▲]

SNR-Based GNSS-R for Coastal Sea-Level Altimetry

in Geosciences (2021), 11(9 391),

Geodetic Global Navigation Satellite System reflectometry (GNSS-R) uses ground-based signals of opportunity to retrieve sea levels at an intermediate spatial scale. Geodetic GNSS-R is based on the ... [more ▼]

Geodetic Global Navigation Satellite System reflectometry (GNSS-R) uses ground-based signals of opportunity to retrieve sea levels at an intermediate spatial scale. Geodetic GNSS-R is based on the simultaneous reception of Line-of-Sight (LoS) and its coherent GNSS sea surface reflection (non-LOS) signals. The scope of this paper is to present geodetic GNSS-R applied to sea level altimetry. Signal-to-Noise Ratio (SNR) measurements from a Commercial Off-The-Shelf (COTS) geodetic-quality GNSS station at the Haiti Coast Guard Base in Port-au-Prince is used to retrieve sea levels in the International Terrestrial Reference Frame 2014 (ITRF2014). The GNSS-R sea levels are compared with those of the OTT Radar Level Sensor (RLS) installed vertically below the GNSS antenna. The Root-Mean-Square Error (RMSE) between the geodetic GNSS-R sea levels and OTT RLS records is 3.43 cm, with a correlation of 0.96. In addition, the complex differences between the OTT RLS records and 15-min GNSS-R sea levels using Global Positioning System (GPS) and Globalnaya Navigazionnaya Sputnikovaya Sistema (or Global Navigation Satellite System; GLONASS) signals for all the eight major tidal constituents are in mm-level agreement. Therefore, geodetic GNSS-R can be used as a complementary approach to the conventional method for sea level studies in a stable terrestrial reference frame. [less ▲]

Renewable electricity business models in a post feed-in tariff era

in Energy (2021), 216

To expand intermittent renewable electricity sources (RESs), worldwide energy policy makers have introduced fixed feed-in tariffs (FITs). However, FITs typically expire after a limited time period. Due to ... [more ▼]

To expand intermittent renewable electricity sources (RESs), worldwide energy policy makers have introduced fixed feed-in tariffs (FITs). However, FITs typically expire after a limited time period. Due to the intermittent electricity supply of RES, market distortions, and insufficient flexibility options, exclusive participation in wholesale electricity markets might not be a viable business model for RES that no longer receive a FIT. Thus, it remains unclear which RES business models (RBMs) ensure a viable operation of RES in the post FIT era. To close this research gap, we present a typology encompassing five RBM archetypes: wholesale electricity market (1), physical power purchase agreements (2), nonphysical power purchase agreements (3), self-consumption (4), and on-site power-2-X (5). The typology includes three additional service layers, which may enhance the profitability of RBM archetypes by opening up additional revenue streams: infrastructure services (1), electricity storage services (2), and ancillary services (3). We highlight the need for new approaches to quantify the viability of RBM archetypes and services layers under different regulatory, technological, and market conditions. To prevent the imminent decommissioning of existing RESs, policy makers must shape the next era of the energy transition, weighting the implications of market-based and intervention-based energy policy approaches. [less ▲]

Diagnostics and correction of batch effects in large-scale proteomic studies: a tutorial.

in Molecular systems biology (2021), 17(8), 10240

Advancements in mass spectrometry-based proteomics have enabled experiments encompassing hundreds of samples. While these large sample sets deliver much-needed statistical power, handling them introduces ... [more ▼]

Advancements in mass spectrometry-based proteomics have enabled experiments encompassing hundreds of samples. While these large sample sets deliver much-needed statistical power, handling them introduces technical variability known as batch effects. Here, we present a step-by-step protocol for the assessment, normalization, and batch correction of proteomic data. We review established methodologies from related fields and describe solutions specific to proteomic challenges, such as ion intensity drift and missing values in quantitative feature matrices. Finally, we compile a set of techniques that enable control of batch effect adjustment quality. We provide an R package, "proBatch", containing functions required for each step of the protocol. We demonstrate the utility of this methodology on five proteomic datasets each encompassing hundreds of samples and consisting of multiple experimental designs. In conclusion, we provide guidelines and tools to make the extraction of true biological signal from large proteomic studies more robust and transparent, ultimately facilitating reliable and reproducible research in clinical proteomics and systems biology. [less ▲]

A platform for experimental precision medicine: The extended BXD mouse family.

in Cell systems (2021), 12(3), 235-2479

The challenge of precision medicine is to model complex interactions among DNA variants, phenotypes, development, environments, and treatments. We address this challenge by expanding the BXD family of ... [more ▼]

The challenge of precision medicine is to model complex interactions among DNA variants, phenotypes, development, environments, and treatments. We address this challenge by expanding the BXD family of mice to 140 fully isogenic strains, creating a uniquely powerful model for precision medicine. This family segregates for 6 million common DNA variants-a level that exceeds many human populations. Because each member can be replicated, heritable traits can be mapped with high power and precision. Current BXD phenomes are unsurpassed in coverage and include much omics data and thousands of quantitative traits. BXDs can be extended by a single-generation cross to as many as 19,460 isogenic F1 progeny, and this extended BXD family is an effective platform for testing causal modeling and for predictive validation. BXDs are a unique core resource for the field of experimental precision medicine. [less ▲]

Bildung für nachhaltige Entwicklung als Kompetenzorientierung

in KiTa aktuell HRS - Fachzeitschrift für Leitungen, Fachkräfte und Träger der Kindertagesbetreuung (2021), 29(9), 197